New study aims to understand genetic synergy in cleft palate

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New study aims to understand genetic synergy in cleft palate


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Studies have shown that the IRF6 gene contributes to about 12–18 per cent of the risk of developing a cleft palate—more than any other gene identified thus far. (Photograph: Fleckstone/Shutterstock)
Dental Tribune International

By Dental Tribune International

Mon. 31. July 2017


WASHINGTON, D.C., USA: As all phases of fetal development, palate growth is a marvel of nature. In one part of the process, ledges of tissue on the sides of the face grow downwards on both sides of the tongue, then upwards, fusing at the midline at the top of the mouth. The majority of the time, this process is completed correctly. However, a part of the process goes awry for around 2,650 babies born in the United States each year with cleft palates and for the thousands more worldwide that are also born with the defect.

For nearly two decades, researchers have known that a gene called IRF6 is involved in palate formation. IRF6 is active in epithelial tissue—the tissue that lines cavities and surfaces throughout the body—including the periderm, a tissue that lines the mouth cavity and plays an important role in fetal development. A recent study conducted by researchers from the Children's National Health System aimed to understand how this key gene might interact with other genes that are also active during fetal development. The researchers were particularly interested in genes that work together in a cascade of activity known as the tyrosine kinase receptor signaling pathway.

Since this pathway includes a large group of genes, Dr. Youssef Kousa and his colleagues reasoned that they could find out whether IRF6 interacts with this pathway by looking whether it interacts with the last gene of the cascade called SPRY4. In order to do this, the research team worked with experimental models that had mutations in IRF6, SPRY4 or both. The scientists hypothesized that if these two genes should interact with both carrying mutations at the same time, it would result in a dramatically different outcome than in an individual who carried mutations in just one gene.

Kousa says the research team plans to continue exploring this interaction to better understand the flow of events that lead from perturbations in the genes to the formation of a cleft palate. Some of the questions they would like to answer include, which gene or genes in the tyrosine kinase receptor signaling pathway specifically interact with IRF6. Since SPRY4 represents just the end of the pathway, the other genes that are present earlier in the pathway are probably the real culprits responsible for problems in palate formation. They also need to verify whether these interactions take place in humans in the same way they occur in preclinical models.

These findings could aid in personalized prenatal counseling, diagnosis and screenings related to cleft palates, as well as help prevent this condition during pregnancy. “Gaining a better understanding of this gene might help us to eventually address deficits or perturbations in the system that creates the palate,” Kousa added.

The study, titled “IRF6 and SPRY4 signaling interact in periderm development”, was published online on 21 July in the Journal of Dental Research.

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